Autism spectrum disorders (ASDs) are pervasive neurodevelopmental disorders diagnosed in early childhood when acquired skills are lost or the acquisition of new skills becomes delayed. ASDs onset in early childhood and are associated with varying degrees of dysfunctional communication and social skills, in addition to repetitive and stereotypic behaviors. In many cases (25%-50%), a period of seemingly normal development drastically shifts directions as acquired skills are lost or the acquisition of new skills becomes delayed.
In recent years, the number of people with an ASD has increased considerably to approximately 1 in 150 children, but it is not clear whether this increase is because of a higher prevalence of the disorder, improved awareness by clinicians, or a combination of both.
One proposed cause for the increased number of people with an ASD is an increase in exposure to mercury from environmental and medicinal sources. Mercury exposure causes immune, sensory, neurological, motor, and behavioral dysfunction similar to symptoms associated with autism. Methyl mercury ingestion from fish has been previously linked to neurological damage. Ethyl mercury linked to thiosalicylate, known as thimerosal, has been used extensively as a preservative in vaccines and has been suspected to contribute to the pathogenesis of autism. Mercury chloride (HgCl2) is known to induce the release of bioactive molecules such as histamine and vascular endothelial growth factor (VEGF) that could disrupt the protective blood-brain barrier (BBB).
A number of studies have reported that patients with ASDs have in their blood antibodies against brain proteins. Brain blood vessels can become leaky (permeable) at some point during a child's development and allow circulating immune cells to be exposed to brain proteins that were mistaken by the immune system as foreign. As a result, antibodies are made against those brain proteins. Such antibodies against brain proteins can disrupt normal brain function and, alone or together with other circulating immune cell-derived destructive molecules, can contribute to brain damage and to the pathogenesis of ASDs. Moreover, increased brain blood vessel leakage can increase intracranial pressure and contribute to macrocephaly reported in many children with ASDs, thus further compromising brain function.
There is currently no explanation for what causes the brain blood vessels to become leaky, i.e., what causes the disruption of the blood-brain barrier (BBB). Identification of molecules that can make brain blood vessels leak could lead to the development of diagnostic biomarkers and serve as targets for treating ASDs. Preventing brain blood vessel leakage in susceptible children, or reversing brain blood vessel leakage in children who have already developed ASDs, could provide a novel therapeutic intervention.
Currently, there are no known defined mechanisms of pathogenesis, diagnostic biomarkers, or curative therapy available for ASDs. An important need therefore exists for methods and compositions that are effective to screen for and treat ASDs. Various embodiments of the invention address these needs.